KR101665901B1 - 인공 생체 입자 및 그 제조 방법 - Google Patents
인공 생체 입자 및 그 제조 방법 Download PDFInfo
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Abstract
볼트 (2) 의 웨이스트 (8) 를 구성하는 MVP (3) 의 N 말단 각각에 류신 지퍼 (4) 가 도입된 것을 특징으로 하는 인공 생체 입자 (1), 그리고, 류신 지퍼 유전자를 MVP 유전자의 N 말단이 되는 측에 도입하여 발현시키는 인공 생체 입자 (1) 의 제조 방법에 의해, 드러그 딜리버리 시스템 (DDS) 등에 대한 응용이 가능한 나노캡슐로서 사용될 수 있는, 그 큰 내부 공간을 유효하게 이용할 수 있는 볼트를 사용한 신규 인공 생체 입자 및 그 제조 방법이 제공된다.
Description
본 발명은 드러그 딜리버리 시스템 (DDS) 등에 대한 응용이 가능한 나노캡슐로서 사용될 수 있는, 볼트 (Vault) 를 사용한 신규 인공 생체 입자 및 그 제조 방법에 관한 것이다.
볼트 (2) 는 입자 사이즈가 40 ㎚ × 40 ㎚ × 67 ㎚ 인 난형의 거대한 생체 입자로, 세포 내에서 최대 분자량을 갖는 핵산-단백질 복합체이다 (도 2 를 참조). 생체 내에 존재하는 볼트 (2) 는 3 종류의 단백질 (MVP (Major Vault Protein), VPARP (vault poly(ADP-ribose)polymerase), TEP1 (telomerase-associated protein-1)) 과 1 종류의 RNA 로 구성되어 있다. 볼트 (2) 는 주성분인 분자량 약 100 kDa 의 MVP (3) 가 39 개 모여 사발형의 절반의 볼트 (각 부위는 캡 (5), 숄더 (6), 보디 (7) 및 웨이스트 (8) 로 칭해진다) 를 형성하고, 그들 2 개가 사발의 가장자리와 가장자리를 맞추도록 웨이스트 (8) 에 있어서 회합됨으로써 난형 입자의 외각이 형성된다. MVP 이외의 성분에 대해서는, 외각에 의해 형성된 내부 공간에 존재한다.
볼트 (2) 의 외각을 구성하는 MVP (3) 는 역평행 β 시트로 형성되는 9 개의 반복 구조 (3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i) 와, 숄더 (6), 캡 헬릭스 (9) 및 캡 링 (10) 의 합계 12 개의 도메인으로 구성되어 있고 (도 3), 캡 헬릭스 (9) 의 도메인간의 분자간 소수 결합이 사발형을 한 절반의 볼트의 형성에 중요하다. 2 개의 절반의 볼트는 MVP (3) 의 N 말단끼리를 회합함으로써 난형의 볼트 입자를 형성하고, 그 회합은 이온 결합과 짧은 분자간 β 시트만이라는 매우 약한 상호 작용에 의해서만 형성되어 있다. 이와 같은 볼트의 구조 정보 및 입자 형성의 메커니즘은 본 발명자가 2009년에 래트 간장 유래 볼트의 전체 구조 결정에 성공하여 분명해졌다 (예를 들어, Hideaki Tanaka et al., 「The Structure of Rat Liver Vault at 3.5 Angstrom Resolution」, Science, Vol.323, pp.384-388 (2009) (비특허문헌 1) 을 참조).
볼트는, 그 주성분인 MVP 를 곤충 세포로 발현시키면, 생체 내와 동일한 난형의 입자가 형성되는 것은 이전부터 알려져 있었다 (예를 들어, Andrew G.Stephen et al., 「Assembly of Vault-like Particles in Insect Cells Expressing Only the Major Vault Protein」, The Journal of Biological Chemistry, Vol.276, No.26, pp.23217-23220 (2001) (비특허문헌 2) 을 참조). 볼트는, 그 특징적인 형태 때문에, 나노캡슐로서 이용하는 것에 의한 드러그 딜리버리 시스템 (DDS) 의 개발이 진행되고 있다 (예를 들어, Valerie A. Kickhoefer et al., 「Engineering of vault nanocapsules with enzymatic and fluorescent properties」, PNAS, Vol.102, No.12, pp.4348-4352 (2005) (비특허문헌 3), Valerie A. Kickhoefer et al., 「Targeting Vault Nanoparticles to Specific Cell Surface Receptors」, ACS nano, 3 (1): 27-36.doi: 10.1021/nn800638x (2009) (비특허문헌 4) 를 참조).
또, 예를 들어 일본 공표특허공보 2013-509202호 (특허문헌 1) 에서는, MVP 그리고 융합 단백질 또한 mINT 및 관심 대상의 단백질 (사이토카인) 을 갖는 재조합 입자인 볼트 입자를, 세포 혹은 종양 또는 대상에 대한 관심 대상의 단백질의 송달을 위해서 사용하는 것이 개시되어 있다. 그 외에, 예를 들어 일본 공표특허공보 2007-508846호 (특허문헌 2) 에서는, 폴리펩티드로 패키징된, 폴리뉴클레오티드를 송달하기 위한 조성물로서, 폴리뉴클레오티드 결합 영역으로서 류신 지퍼를 갖는 기술이 개시되어 있다.
종래의 방법에서는, 약제의 입자 내부로의 도입에, 볼트의 구성 성분으로 입자 내부에 존재하는 VPARP 의 C 말단 160 잔기 (INT 도메인:MVP 와 결합한다) 를 태그로서 이용하고 있다. 이것은 입자 내부에 약제를 유지시켜 두기 위해서이기도 하다. 그러나, 이 방법에서는, 볼트의 큰 내부 공간을 충분히 다 활용할 수 없었다.
Hideaki Tanaka et al., 「The Structure of Rat Liver Vault at 3.5 Angstrom Resolution」, Science, Vol.323, pp.384-388 (2009)
Andrew G.Stephen et al., 「Assembly of Vault-like Particles in Insect Cells Expressing Only the Major Vault Protein」, The Journal of Biological Chemistry, Vol.276, No.26, pp.23217-23220 (2001)
Valerie A. Kickhoefer et al., 「Engineering of vault nanocapsules with enzymatic and fluorescent properties」, PNAS, Vol.102, No.12, pp.4348-4352 (2005)
Valerie A. Kickhoefer et al., 「Targeting Vault Nanoparticles to Specific Cell Surface Receptors」, ACS nano, 3 (1):27-36.doi: 10.1021/nn800638x (2009)
본 발명은 상기 과제를 해결하기 위해서 이루어진 것으로서, 그 목적으로 하는 바는, 드러그 딜리버리 시스템 (DDS) 등에 대한 응용이 가능한 나노캡슐로서 사용될 수 있는, 그 큰 내부 공간을 유효하게 이용할 수 있는 볼트를 사용한 신규 인공 생체 입자 및 그 제조 방법을 제공하는 것이다.
본 발명의 인공 생체 입자는 볼트의 웨이스트를 구성하는 MVP 의 N 말단 각각에 류신 지퍼가 도입된 것을 특징으로 한다.
본 발명의 인공 생체 입자는 MVP 의 N 말단과 류신 지퍼 사이에 링커가 개재되어 있는 것이 바람직하다. 이 경우, 링커는 3 ∼ 6 개의 글리신인 것이 보다 바람직하다.
본 발명의 인공 생체 입자에 있어서, 류신 지퍼는 효모의 전사 활성화 인자 GCN4 유래인 것이 바람직하다.
본 발명은 또, 상기 서술한 본 발명의 인공 생체 입자를 제조하는 방법으로서, 류신 지퍼 유전자를 MVP 유전자의 N 말단이 되는 측에 도입하여 발현시키는 인공 생체 입자의 제조 방법에 대해서도 제공한다.
본 발명의 인공 생체 입자의 제조 방법에 있어서, MVP 유전자와 류신 지퍼 유전자를, 제한 효소 사이트를 개재하지 않고, 링커를 코드하는 유전자로 연결시키는 것이 바람직하다.
본 발명의 인공 생체 입자의 제조 방법에 의해, 종래와 비교하여 현격히 고수율로 인공 생체 입자를 얻는 것이 가능해졌다. 본 발명의 인공 생체 입자는 그 내부 공간을 유효하게 이용할 수 있는 DDS 등에 이용 가능한 나노캡슐로서 기대되고, 본 발명에 의해 수량이 한 자릿수 오름으로써, 대폭적인 비용 삭감으로 이어진다. 또, 본 발명의 인공 생체 입자를 기반으로 하여, pH 의존으로 가역적인 개폐 제어 가능한 입자의 개발이 진행되는 것을 기대할 수 있다.
도 1 은 본 발명의 인공 생체 입자 (1) 에 있어서의, 볼트 (2) 를 구성하는 MVP (3) 의 N 말단 (3a) 과 류신 지퍼 (4) 의 결합에 대해 개념적으로 나타내는 모식도이다.
도 2 는 본 발명의 인공 생체 입자 (1) 에 사용되는 볼트 (2) 를 모식적으로 나타내는 도면이다.
도 3 은 볼트 (2) 를 구성하는 MVP (3) 를 모식적으로 나타내는 도면이다.
도 4 는 본 발명의 인공 생체 입자 (1) 를 나노캡슐로서 응용한 경우를 모식적으로 나타내는 도면이다.
도 5 는 본 발명의 인공 생체 입자 (1) 를 나노캡슐로서 응용한 드러그 딜리버리 시스템의 일례를 모식적으로 나타내는 도면이다.
도 6 의 좌측은 파쇄 후의 SDS-PAGE 의 결과를 나타내는 사진이며, LZMVP_Gly3 에 대한 상청 (레인 A), 침전 (레인 B), LZMVP_Gly6 에 대한 상청 (레인 C), 침전 (레인 D) 을 각각 나타내고 있다. 또, 도 6 의 우측은 자당 밀도 구배 원심 분리 후의 SDS-PAGE 의 결과를 나타내는 사진이며, 좌측의 군 a 가 LZMVP_Gly3 에 대한 결과, 우측의 군 b 가 LZMVP_Gly6 에 대한 결과를 각각 나타내고 있다.
도 7 은 LZMVP_Gly3 에 대해 최종 정제 표품을 나타내는 전자 현미경 사진이다.
도 2 는 본 발명의 인공 생체 입자 (1) 에 사용되는 볼트 (2) 를 모식적으로 나타내는 도면이다.
도 3 은 볼트 (2) 를 구성하는 MVP (3) 를 모식적으로 나타내는 도면이다.
도 4 는 본 발명의 인공 생체 입자 (1) 를 나노캡슐로서 응용한 경우를 모식적으로 나타내는 도면이다.
도 5 는 본 발명의 인공 생체 입자 (1) 를 나노캡슐로서 응용한 드러그 딜리버리 시스템의 일례를 모식적으로 나타내는 도면이다.
도 6 의 좌측은 파쇄 후의 SDS-PAGE 의 결과를 나타내는 사진이며, LZMVP_Gly3 에 대한 상청 (레인 A), 침전 (레인 B), LZMVP_Gly6 에 대한 상청 (레인 C), 침전 (레인 D) 을 각각 나타내고 있다. 또, 도 6 의 우측은 자당 밀도 구배 원심 분리 후의 SDS-PAGE 의 결과를 나타내는 사진이며, 좌측의 군 a 가 LZMVP_Gly3 에 대한 결과, 우측의 군 b 가 LZMVP_Gly6 에 대한 결과를 각각 나타내고 있다.
도 7 은 LZMVP_Gly3 에 대해 최종 정제 표품을 나타내는 전자 현미경 사진이다.
도 1 은 본 발명의 인공 생체 입자 (1) 에 있어서의, 볼트 (2) 를 구성하는 MVP (3) 의 N 말단 (3a) 과 류신 지퍼 (4) 의 결합에 대해 개념적으로 나타내는 모식도이다. 또, 도 2 는 본 발명의 인공 생체 입자 (1) 에 사용되는 볼트 (2) 를 모식적으로 나타내는 도면이고, 도 3 은 볼트 (2) 를 구성하는 MVP (3) 를 모식적으로 나타내는 도면이다. 상기 서술한 바와 같이, 볼트 (2) 는 주성분인 MVP (3) 가 39 개 모여 사발형의 절반의 볼트 (각 부위는 캡 (5), 숄더 (6), 보디 (7) 및 웨이스트 (8) 로 칭해진다) 를 형성하고, 그들 2 개가 사발의 가장자리와 가장자리를 맞추도록, 웨이스트 (8) 에 있어서 회합됨으로써 난형 입자의 외각이 형성된다 (도 2). 볼트 (2) 의 외각을 구성하는 MVP (3) 는 역평행 β 시트로 형성되는 9 개의 반복 구조 (3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i) 와, 숄더 (6), 캡 헬릭스 (9) 및 캡 링 (10) 의 합계 12 개의 도메인으로 구성되어 있다 (도 3). 본 발명의 인공 생체 입자 (1) 는 볼트 (2) 의 웨이스트 (8) 를 구성하는 MVP (3) 의 N 말단 각각에 류신 지퍼 (4) 가 도입된 것을 특징으로 한다.
본 발명의 인공 생체 입자 (1) 는 MVP (3) 의 N 말단과 류신 지퍼 (4) 사이에 링커가 개재되어 있는 것이 바람직하다. 이와 같은 링커가 개재되어 있음으로써, 인공 생체 입자 (1) 에 있어서의 류신 지퍼 (4) 의 움직임 자유도가 담보된다.
본 발명의 인공 생체 입자 (1) 에 있어서의 MVP (3) 의 N 말단과 류신 지퍼 (4) 사이의 링커는 작은 아미노산이 1 ∼ 6 개 직사슬형으로 연이어 형성되는 것이 바람직하다. 링커를 형성하는 아미노산의 수가 1 ∼ 6 개인 어떠한 경우라 하더라도 류신 지퍼 (4) 를 갖는 인공 생체 입자 (1) 는 발현되지만, 보다 발현량이 많고, 얻어지는 인공 생체 입자 (1) 가 균일하다는 관점에서, 나아가서는, 류신 지퍼 (4) 의 움직임 자유도의 관점에서, 링커는 작은 아미노산이 3 ∼ 6 개 직사슬형으로 연이어 형성되는 것이 바람직하다. 링커를 구성하는 아미노산으로는, 예를 들어 글리신, 알라닌 등의 측사슬이 작은 아미노산을 들 수 있다. 후술하는 본 실험예에서는, 3 개 또는 6 개의 직사슬형의 글리신으로 링커를 형성한 예를 나타내고 있다.
류신 지퍼 (4) 는 약 30 잔기의 아미노산으로 구성되는 α-헬릭스 2 개가 서로의 류신 잔기에서 소수 결합됨으로써 형성되는 지퍼와 같은 모티프이다. 본 발명에 있어서의 류신 지퍼 (4) 로는, 예를 들어 효모의 전사 활성화 인자 GCN4 유래의 류신 지퍼, 그 이외의 다른 단백질 유래의 류신 지퍼에 대해서도 특별히 제한 없이 사용할 수 있다. 그 중에서도, 1991년에 효모의 전사 활성화 인자 GCN4 유래의 류신 지퍼의 X 선 결정 구조가 1.8 Å 분해능에서 결정되어 있고, 33 잔기의 아미노산으로 구성된 펩티드가 서로의 류신 잔기에서 소수 결합됨으로써, 강고한 코일드 코일을 형성하는 것이 원자 레벨에서 밝혀져 있는 점으로부터, 효모의 전사 활성화 인자 GCN4 유래의 류신 지퍼가 바람직하게 사용될 수 있다.
이와 같은 본 발명의 인공 생체 입자에 의하면, 그 내부 공간을 유효하게 이용할 수 있는 DDS 등에 이용 가능한 나노캡슐로서 기대되고, 본 발명에 의해 수량이 한 자릿수 오름으로써, 대폭적인 비용 삭감으로 이어진다. 또, 본 발명의 인공 생체 입자를 기반으로 하여, pH 의존으로 가역적인 개폐 제어 가능한 입자의 개발이 진행되는 것을 기대할 수 있다.
여기서 도 4 는 본 발명의 인공 생체 입자 (1) 를 나노캡슐로서 응용한 경우를 모식적으로 나타내는 도면이고, 도 5 는 본 발명의 인공 생체 입자 (1) 를 나노캡슐로서 응용한 DDS 의 일례를 모식적으로 나타내는 도면이다. 본 발명의 인공 생체 입자 (1) 에 의해, 예를 들어, MVP 의 N 말단에 붙인 류신 지퍼에 시스테인 잔기를 도입함으로써, 도 4 에 나타내는 바와 같이, 중성 조건에서는 디술파이드 결합에 의해 안정적인 난형 입자를 형성하고, 산성 조건하에서는 디술파이드 결합의 개열에 의해 알을 딱 절반으로 나눈 것처럼 열리는 듯한, pH 의존으로 가역적으로 개폐 제어 가능한 나노캡슐을 개발할 수 있을 가능성이 있다. 이와 같은 나노캡슐을 사용함으로써, 예를 들어, 도 5 에 나타내는 바와 같이, 산성 조건하에서 약제 (11) 를 볼트 (2) 의 내부 공간에 넣어 두고, 이것을 투여함으로써, 표적 세포 (13) 의 표면의 특이적인 항원 (12) 과, 볼트 (2) 의 표면에 미리 부착된 항체 (Fab) 의 항원 항체 반응에 의해 나노캡슐이 표적 세포 (13) 내에 도입되고, 엔도솜 (14) 내에서 산성 조건이 됨으로써 나노캡슐이 열리고 약제 (11) 가 방출된다는 것과 같은 DDS 도 생각될 수 있다. 이와 같은 본 발명의 인공 생체 입자는, 그 내부에 매우 큰 공간이 있기 때문에, 유전자 치료시의 캐리어로서도 유망할 것으로 생각된다.
또, 본 발명의 인공 생체 입자 (1) 는 화장품 등의 성분을 가두고, 피부 안쪽까지 침투시키는 나노캡슐로서의 이용 등도 생각할 수 있다.
또, 최근, 단백질 복합체의 내부 공간을 주형으로서 이용하여, 금속을 중합시키고, 그들을 규칙적으로 배열시킴으로써, 극소 반도체의 베이스가 되는 기판을 만드는 기술 등도 확립되어 오고 있다. 현재는, 페리틴 등의 구상 단백질이 사용되고 있지만, 본 발명의 인공 생체 입자 (1) 를 이용함으로써, 볼트 (2) 와 같은 타원을 한 입자를 사용함으로써 지금까지 없던 신규 기판을 제조할 수 있을 가능성이 있다.
본 발명은 또, 류신 지퍼 유전자를 MVP 유전자의 N 말단이 되는 측에 도입하여 발현시키는 것을 특징으로 하는, 인공 생체 입자 (1) 의 제조 방법에 대해서도 제공한다. 이로써, 실험예에 있어서 후술하는 바와 같이, 야생형 MVP (W-MVP) 로 형성되는 W-볼트의 곤충 세포를 사용한 종래의 발현계와 비교하면, 10 배 이상이라는 현격히 높은 수율로 본 발명의 인공 생체 입자 (1) 를 얻을 수 있다. 류신 지퍼 유전자 및 MVP 유전자의 염기 배열은 이미 공지이며, 종래 공지된 유전자 공학 수법을 적절히 조합함으로써, 류신 지퍼 유전자를 MVP 유전자의 N 말단이 되는 측에 도입할 수 있다. 후술하는 실험예에서는, 효모의 전사 활성화 인자 GCN4 로부터 잘라내고 정제된 류신 지퍼 유전자의 프래그먼트, 마찬가지로 잘라내고 정제된 래트 유래의 MVP 유전자의 프래그먼트를 (후술하는 링커를 개재하여) 라이게이션시킨 예를 나타내고 있다.
류신 지퍼 유전자를 MVP 유전자의 N 말단이 되는 측에 도입한 것을 발현시키는 세포로는 특별히 제한되지 않지만, 곤충 세포, 곤충 세포보다 고등인 생물의 세포가 예시된다. 곤충 세포보다 하등인, 예를 들어 대장균을 사용한 경우에는, 생체 입자가 잘 형성되지 않는 경우가 있는 것이 알려져 있어, 당 분야에서 통상 사용되고 있는 곤충 세포를 사용하여 발현시키는 것이 바람직하다. 곤충 세포의 구체예로는, Sf9 가 예시된다. 발현된 인공 생체 입자는 종래 공지된 적절한 방법에 의해 정제될 수 있다.
본 발명의 인공 생체 입자 (1) 의 제조 방법에 있어서는, MVP 유전자와 류신 지퍼 유전자를, 제한 효소 사이트를 개재하지 않고, 링커를 코드하는 유전자로 연결시키는 것이 바람직하다. 상기 서술한 효모의 전사 활성화 인자 GCN4 유래의 류신 지퍼 유전자의 프래그먼트, 래트 유래의 MVP 유전자를 사용한 경우, 그것을 연결시키고자 하면, 그 사이에 EcoRI 의 사이트 (GAATTC) 가 남아, 볼트 입자의 형성을 저해할 가능성이 있다. 후술하는 실험예에서는, EcoRI 사이트를 가장 작은 측사슬을 갖는 아미노산글리신을 3 잔기 또는 6 잔기 연결한 Gly 링커로 치환한 후, 곤충 세포로 발현시켰다. 구체적으로는, 도입시키고자 하는 링커에 따라 프라이머를 설계하고, PCR 후, 정제한 프래그먼트를, MVP 유전자의 N 말단과 류신 지퍼 유전자 사이에 개재시키도록 라이게이션시키면 된다.
또한, 본 발명의 인공 생체 입자 (1) 의 제조 방법에 있어서도, 류신 지퍼, 링커 등, 바람직한 것은 인공 생체 입자 (1) 에 대해 상기 서술한 바와 같다.
이하, 실험예를 들어 본 발명을 보다 상세하게 설명하지만, 본 발명은 이들에 한정되는 것은 아니다.
<실험예>
[1] 곤충 세포 Sf9 에 의한 야생형 MVP (W-MVP) 의 대량 발현계의 구축
[A] W-MVP 를 클로닝한 재조합 바큘로바이러스 게놈 (Bacmid DNA) 의 조제
이하의 순서로 작업을 실시하였다.
(1) 래트 간장 유래 MVP (W-MVP) 의 DNA 를 EcoRI 와 SphI 의 제한 효소 사이트에 의해, pFastBac 벡터에 도입하였다.
(2) 얻어진 pFastBac 를 대장균 (DH5α) 으로 형질 전환하고, Ampicillin (100 ㎍/㎖) 이 든 LB 플레이트에 뿌리고, 37 ℃ 에서 24 시간 정치 배양하였다.
(3) 콜로니 수 개를 백금 루프 등으로 골라내고, 콜로니 PCR 로 목적으로 하는 유전자가 증폭되는지를 확인하였다.
(4) 상기 (3) 에서, 유전자의 증폭을 확인할 수 있었던 콜로니를 Ampicillin (100 ㎍/㎖) 이 든 LB 액체 배지 5 ㎖ 에 식균하고, 37 ℃ 에서 하룻밤 진탕 배양하였다.
(5) 하룻밤 배양한 대장균 (DH5α) 으로부터, QIAGEN 사의 QIAprep Spin Miniprep Kit 를 사용하여 W-MVP 가 클로닝된 pFastBac 를 정제하였다.
(6) W-MVP 가 클로닝된 pFastBac 0.1 ㎍ 을 DH10Bac 20 ㎕ 에 첨가하고, 가볍게 혼합한 후, 빙상에서 20 분간 정치하였다.
(7) 42 ℃ 에서 1 분간 히트 쇼크를 실시하고, 빙상에서 2 분간 정치한 후, 200 ㎕ 의 SOC 배지를 첨가하고, 37 ℃ 에서 4 시간 진탕 배양하였다.
(8) 상기 (7) 의 배양액을 kanamycin (50 ㎍/㎖), gentamicin (7 ㎍/㎖), tetracycline (10 ㎍/㎖), X-gal (100 ㎍/㎖), IPTG (50 ㎍/㎖) 가 든 LB 플레이트에 20 ㎕ 뿌리고, 37 ℃ 에서 24 시간 정치 배양하였다 (콜로니의 발색 유무 (청색인지 백색인지) 를 판별할 수 있을 때까지 배양하였다).
(9) 백색의 콜로니를 백금 루프 등으로 골라내고, 새로운 LB 플레이트 (상기와 동일) 에 식균하고, 37 ℃ 에서 하룻밤 정치 배양한 후, 발색 유무를 재확인하였다.
(10) 상기 (9) 에서 재확인한 백색의 콜로니 유래의 대장균 (DH5α) 을 kanamycin (50 ㎍/㎖), gentamicin (7 ㎍/㎖), tetracycline (10 ㎍/㎖) 이 든 LB 액체 배지 5 ㎖ 에 식균하고, 37 ℃ 에서 하룻밤 진탕 배양하였다.
(11) 하룻밤 배양한 대장균 (DH10Bac) 으로부터, QIAGEN 사의 QIAprep Spin Miniprep Kit 를 사용하여 W-MVP 가 클로닝된 Bacmid 를 정제하였다. Bacmid 는 매우 사이즈가 크기 때문에, 정제시, 용출 버퍼는 70 ℃ 로 따뜻하게 한 것을 사용하였다.
[B] W-MVP 를 클로닝한 재조합 바큘로바이러스의 증식 (바이러스액의 제조)
안전 캐비닛 내에서 이하의 순서로 실시하였다.
(1) Invitrogen 사의 Sf900-II 배지 (10 % 혈청 함유) 에서 배양 중인 Sf9 세포 (1.5-2.0 × 106 cell/㎖) 를 15 ㎖ tube 내에서 Sf900-II 배지 (10 % 혈청 함유) 를 사용하여 희석시킴으로써, 농도를 1.2 × 105 cell/㎖ 로 조제하였다.
(2) 12 웰 배양 플레이트에 최종 농도 0.4 × 105 cell/㎖ 로 조제한 세포 배양액을 1 ㎖ 넣었다. 상기 서술한 1.2 × 105 cell/㎖ 의 배양액을 300 ㎕, Sf900-II 배지 (10 % 혈청 함유) 를 700 ㎕ 첨가하여 토탈 1 ㎖ 로 하였다.
(3) 27 ℃ 에서 20 분간 정치하고, 세포를 세포 배양 플레이트의 바닥면에 접착시켰다.
(4) 1.5 ㎖ 튜브 내에서, Grace medium unsupplement 214 ㎕, Cellfectin 8 ㎕, Bacmid 1 ㎍ 을 혼합하고, 안전 캐비닛 내에서 실온, 30 분간 방치하였다 (Cellfectin 은 볼텍스 믹서로 10 초 정도 교반하고 나서 사용).
(5) 상기 (3) 에서의 12 웰 배양 플레이트를 도립 현미경 관찰하여, 세포가 용기의 바닥면에 부착되어 있는 것을 확인하고 나서 배지를 제거하였다 (플레이트를 안쪽으로 기울이면서, 뚜껑을 앞에 세우도록 해 두고, 피펫만으로 빨아냈다).
(6) 배지를 제거한 후, Grace medium unsupplement 1 ㎖ 로 씻었다. 세정액은 버렸다.
(7) 그 후, 세포에 상기 서술한 Bacmid 와 Cellfectin 의 혼합액을 끼얹었다.
(8) 12 웰 플레이트를 밀폐된 타파웨어 내에 넣고, 27 ℃ 에서 4 시간 정치하였다. 타파웨어 내의 습도를 유지하기 위해서 킴와이프 수 장을 순수로 적시고, 0.5 M EDTA 를 1 ㎖ 함유시킨 것을 타파웨어 끝에 놓아 두었다.
(9) 4 시간 후, Grace medium unsupplement (10 % 혈청 함유) 를 400 ㎕ 중층하고, 중간 2 일간, 27 ℃ 에서 배양하였다.
(10) 중간 2 일의 배양 후, 배양액을 1.5 ㎖ 의 튜브에 옮기고, 고속 원심 분리 (4,000×g, 3 min) 에 의해 세포를 침전시켰다. 상청이 바이러스액 (P0) 이 되므로, 이것을 새로운 1.5 ㎖ 의 튜브에 옮겼다. 바이러스액 (P0) 은 차광 필름을 붙인 4 ℃ 의 크로마토그래피 챔버 내에서 보존하였다.
(11) 바닥 면적 25 ㎠ 의 배양 플라스크에, 세포수가 3 × 106 cell 이 되도록 배양액을 첨가하였다 (토탈 5 ㎖ 가 되도록 하였다). 예를 들어, Sf900-II 배지 (10 % 혈청 함유) 에서 배양 중인 Sf9 세포의 세포수가 1 × 106 cell/㎖ 인 경우, 배양액 3 ㎖ 에 Sf900-II 배지 (10 % 혈청 함유) 2 ㎖ 를 첨가하여 5 ㎖ 로 한 것을 배양 플라스크에 넣었다.
(12) 27 ℃ 에서 15 분간 정치하고, 세포를 세포 배양 플라스크의 바닥면에 접착시켰다.
(13) P0 의 바이러스액 200 ㎕ 를 첨가하고, 중간 3 일간 배양하였다.
(14) 중간 3 일의 배양 후, 바이러스액 (P1) 을 회수하기 전에 바닥 면적 75 ㎠ 의 배양 플라스크에 세포수가 9 × 106 cell 이 되도록 배양액을 첨가하였다 (토탈 15 ㎖ 가 되도록 하였다). 6 × 105 cell/㎖ 의 배양액을 15 ㎖ 준비하면, 토탈 세포수가 9 × 106 cell 이 된다.
(15) 27 ℃ 에서 15 분간 정치하고, 세포를 세포 배양 플라스크의 바닥면에 접착시켰다.
(16) 바이러스액 (P1) 을 회수하기 전에, 상기 서술한 바닥 면적 25 ㎠ 의 배양 플라스크로부터, 피펫을 사용하여 0.5 ㎖ 의 상청액을 취출하고, 상기 (14) 의 배양액에 첨가하였다 (컨태미네이션 방지를 위해). 그 후, 배양액을 27 ℃ 에서 중간 3 일간 배양하였다.
(17) 나머지 배양액을 피펫으로 빨아들이거나 내뱉거나 하면서, 플라스크 바닥면에 부착된 세포를 떼어내고, 15 ㎖ 의 튜브에 옮겨 고속 원심 분리 (4,000×g, 3 min) 에 의해 세포를 침전시켰다. 상청이 바이러스액 (P1) 이 되므로, 이것을 새로운 15 ㎖ 의 튜브에 옮겼다. 침전으로서 떨어진 Sf9 세포는 발현 체크용으로서 -80 ℃ 에서 동결 보존하였다. 바이러스액 (P1) 은 차광 필름을 붙인 4 ℃ 의 크로마토그래피 챔버 내에서 보존하였다.
(18) 바닥 면적 75 ㎠ 의 배양 플라스크에서의 배양으로 중간 3 일이 지나면, 배양액을 피펫으로 빨아들이거나 내뱉거나 하면서, 플라스크 바닥면에 부착된 세포를 떼어내고, 50 ㎖ 의 튜브에 옮겨 고속 원심 분리 (4,000×g, 3 min) 에 의해 세포를 침전시켰다. 상청이 바이러스액 (P2) 이 되므로, 이것을 새로운 50 ㎖ 의 튜브에 옮겼다. 침전으로서 떨어진 Sf9 세포는 발현 체크용으로서 -80 ℃ 에서 동결 보존하였다. 바이러스액 (P2) 은 차광 필름을 붙인 4 ℃ 의 크로마토그래피 챔버 내에서 보존하였다.
(19) 1 ℓ 의 스피너 플라스크에 1 × 106 cell/㎖ 의 배양액을 300 ㎖ 준비하고, 바이러스액 (P2) 을 3 ㎖ (배지의 1 % 량) 첨가하여 27 ℃ 에서 중간 3 일 배양하였다.
(20) 중간 3 일 배양 후, 배양액을 원심 튜브에 옮겨 고속 원심 분리 (4,000×g, 30 min) 에 의해 세포를 침전시켰다. 상청이 바이러스액 (P3) 이 되므로, 이것을 새로운 500 ㎖ 의 미디엄 병에 옮겼다. 이 때에 사용하는 원심 튜브, 원심 튜브의 뚜껑, 미디엄 병은 알루미늄 호일로 감싸 오토클레이브에 의해 멸균해 두었다. 침전으로서 떨어진 Sf9 세포는 정제용으로서 -80 ℃ 에서 동결 보존하였다. 바이러스액 (P3) 은 차광 필름을 붙인 4 ℃ 의 크로마토그래피 챔버 내에서 보존하였다.
(21) 3 ℓ 의 스피너 플라스크에 1 × 106 cell/㎖ 의 배양액을 500 ㎖ 준비하고, 바이러스액 (P3) 을 5 ㎖ (배지의 1 % 량) 첨가하여 27 ℃ 에서 중간 3 일 배양하였다.
(22) 중간 3 일 배양 후, 배양액을 원심 튜브에 옮겨 고속 원심 분리 (4,000×g, 30 min) 에 의해 세포를 침전시켰다. 상청이 바이러스액 (P4) 이 되므로, 이것을 새로운 500 ㎖ 의 미디엄 병에 옮겼다. 이 때에 사용하는 원심 튜브, 원심 튜브의 뚜껑, 미디엄 병은 알루미늄 호일로 감싸 오토클레이브에 의해 멸균해 두었다. 침전으로서 떨어진 Sf9 세포는 정제용으로서 -80 ℃ 에서 동결 보존하였다. 바이러스액 (P4) 은 차광 필름을 붙인 4 ℃ 의 크로마토그래피 챔버 내에서 보존하였다.
[2] 곤충 세포 Sf9 에 의한 N 말단에 류신 지퍼를 부가한 MVP (LZ-MVP) 의 대량 발현계의 구축
이하의 순서로 작업을 실시하였다.
(1) 효모균 유래 GCN4 (281 아미노산) 의 아미노산 배열 (배열 번호 1) 249 번째의 아르기닌으로부터 281 번째의 아르기닌까지를 코드하는 DNA (류신 지퍼 유전자) (BamHI 와 EcoRI 의 제한 효소 사이트를 포함한다) (배열 번호 2) (발현되는 류신 지퍼의 아미노산 배열을 배열 번호 3 에 나타낸다) 를 프로메가사의 pGEM-T 벡터에 도입하고, QIAGEN 사의 QIAprep Spin Miniprep Kit 를 사용하여 류신 지퍼가 클로닝된 플라스미드를 정제하였다. pFastBac 에 도입된 류신 지퍼 유전자의 염기 배열 (제한 효소 사이트 (BamHI, EcoRI), 개시 Met 를 포함한다) 을 배열 번호 4 에, 발현되는 류신 지퍼의 아미노산 배열을 배열 번호 5 에 나타낸다.
(2) pGEM-T 벡터로부터, 제한 효소 BamHI 와 EcoRI 를 사용하여 류신 지퍼 유전자를 잘라냈다.
(3) 마찬가지로, 래트 유래의 W-MVP 를 클로닝한 pFastBac 도 제한 효소 BamHI 와 EcoRI 로 처리해 두었다.
(4) 상기 (2) 및 (3) 에서 얻어진 류신 지퍼 유전자의 프래그먼트 및 MVP 유전자의 프래그먼트를 각각 아가로오스 겔 전기 영동하고, 목적으로 하는 밴드를 잘라내고, Quiagen 사의 QIAquick Gel Extraction Kit 를 사용하여 겔로부터 목적물을 정제하였다.
(5) 다카라 바이오사의 DNA Ligation Kit (Mighty Mix) 를 사용하여, 상기 (4) 에서 정제한 양자를 라이게이션시켰다 (라이게이션 후의 염기 배열을 배열 번호 6, 발현되는 류신 지퍼, MVP 의 아미노산 배열을 배열 번호 7, 8 에 나타낸다).
(6) 이하, 상기 서술한 W-MVP 를 클로닝한 재조합 바큘로바이러스 게놈의 조제 (순서 (1)-(11)), 그리고, W-MVP 를 클로닝한 재조합 바큘로바이러스의 증식 (순서 (1)-(20)) 과 동일한 조작을 실시하고, LZ-MVP 를 클로닝한 재조합 바큘로바이러스를 증식하여, 바이러스액 (P4) 을 제조하였다.
[3] LZ-MVP 의 류신 지퍼와 MVP 사이에 대한 글리신 링커의 삽입
상기 구축한 발현계에서는, 류신 지퍼 유전자와 MVP 유전자 사이에 EcoRI 의 사이트 (GAATTC) 가 남아, 볼트 입자의 형성을 저해할 가능성이 있기 때문에, 발명자는, 이들을 가장 작은 측사슬을 갖는 아미노산 (글리신 (Gly)) 을 3 잔기 (Gly3) (아미노산 배열을 배열 번호 9 에 나타낸다) 또는 6 잔기 (Gly6) (아미노산 배열을 배열 번호 10 에 나타낸다) 연결한 Gly 링커로 치환하였다.
(1) 이하의 3 종의 프라이머를 제조하였다 (Gly 를 코드하는 염기 배열은 gcc).
·forward primer (lzmvp_0g_f)
atggcaactgaagaggccat (배열 번호 11)
·forward primer (lzmvp_3g_f)
ggcggcggcatggcaactgaagaggccatcatccgcatc (배열 번호 12)
·reverse primer (lzmvp_3g_r)
GCCAGATTAAAGAAATTAGTTGGCGAACGCggcggcggc (배열 번호 13)
또한, reverse primer 의 상보 배열은 이하와 같다.
gccgccgccgcgttcgccaactaatttctttaatctggc (배열 번호 14)
(2) Gly3 잔기의 링커를 삽입하는 경우에는, lzmvp_0g_f 와 lzmvp_3g_r, Gly6 잔기의 링커를 삽입하는 경우에는, lzmvp_3g_f 와 lzmvp_3g_r 을 프라이머로서 사용하고, 먼저 제조한 LZ-MVP 의 pFastBac 를 주형으로 하여, 토요보 (주) 사 제조의 KOD-plus Mutagenesis kit 를 사용하여 PCR (94 ℃, 2 분 → 98 ℃, 10 초 → 68 ℃, 8 분 (하선부를 10 사이클)) 을 실시하였다.
(3) PCR 후, 토요보 (주) 사 제조의 KOD-plus Mutagenesis kit 에 포함되는 DpnI 를 사용하여 주형 플라스미드를 소화하였다. 1.5 ㎖ 튜브 내에서 PCR product 50 ㎕ 와 DpnI 2 ㎕ 를 혼합하고, 태핑, 스핀 다운한 후에 37 ℃ 에서 1 시간 인큐베이트하였다.
(4) 1.5 ㎖ 튜브 내에서 상기 (3) 의 반응액을 2 ㎕, 멸균수를 7 ㎕, Ligation high 를 5 ㎕, T4 polynucleotide kinase 를 1 ㎕, 여기에 기재한 순서대로 첨가하고, 태핑, 스핀 다운한 후에 16 ℃ 에서 1 시간 인큐베이트하였다.
(5) 대장균 DH5α 50 ㎕ 에 상기 (4) 의 반응액을 5 ㎕ 첨가하고, 빙상에서 30 분 정치하였다.
(6) 42 ℃ 에서 45 초, 히트 쇼크를 실시하였다.
(7) 빙상에서 2 분간 정치하였다.
(8) SOC 배지 450 ㎕ 를 첨가하고, 37 ℃ 에서 1 시간 진탕 배양하였다.
(9) 상기 (8) 의 배양액 50 ㎕ 를 Ampicillin (100 ㎍/㎖) 이 든 LB 플레이트에 뿌렸다.
(10) 37 ℃ 에서 하룻밤 정치 배양하였다.
이 이후는, 상기한 W-MVP 를 클로닝한 재조합 바큘로바이러스 게놈의 조제 순서 (2)-(20) 과 동일한 작업을 실시하여, 류신 지퍼와 MVP 사이에 Gly 링커를 도입한 LZMVP (LZMVP_Gly3, LZMVP_Gly6) 의 바이러스액 (P4) 을 제조하였다.
[4] 볼트 (W-볼트, LZ-볼트) 의 정제
(1) 3 ℓ 의 스피너 플라스크에서 500 ㎖ 의 Sf9 세포를 배양하고, 세포 수가 1 × 106 cell/㎖ 가 된 시점에서, P4 또는 P3 의 바이러스액을 첨가하여 감염시키고 중간 3 일간 배양하였다.
(2) 중간 3 일 배양 후, 배양액을 원심 튜브에 옮겨 고속 원심 분리 (4,000×g, 30 min) 에 의해 세포를 침전시켰다.
(3) 침전시킨 세포를 PBS Buffer 를 사용하여 현탁하고, 현탁액을 원심 튜브에 옮겨 고속 원심 분리 (4,000×g, 30 min) 함으로써 세포를 세정하여, 배지 성분 등을 제거하였다.
(4) 침전으로서 얻어진 세포를 세포 파쇄용 Buffer A (50 mM Tris-HCl (pH 7.5), 75 mM NaCl, 1.5 mM MgCl2, 1 mM DTT, 1 mM PMSF, 프로테아제 저해제·동물 세포용 (나카라이 테스크 (주) 사 제조) 2 개) 100 ㎖ 로 현탁하고, 초음파 파쇄하였다 (TOMY UD-201, OUTPUT 2, DUTY 60, 2 min × 2).
(5) 파쇄액을 고속 원심기 (Beckman HP-26XP, JA25.50 rotor) 를 사용하여, 14,300 rpm, 30 min, 4 ℃ 에서 고속 원심 분리를 실시함으로써, 세포 파쇄 앙금을 침전으로서 제거하였다.
(6) 상청을 초고속 원심기 (Hitachi CP80WX, P45AT rotor) 를 사용하여, 40,000 rpm, 2 시간, 4 ℃ 에서 초고속 원심 분리를 실시함으로써, 볼트 획분을 침전으로서 떨어뜨렸다.
(7) 침전으로서 얻어진 볼트 획분에 정제용 Buffer A (50 mM Tris-HCl (pH 7.5), 75 mM NaCl, 1.5 mM MgCl2, 1 mM DTT, 1 mM PMSF) 를 소량 첨가하고, 다운스 호모게나이저로 현탁하였다.
(8) 상기 (7) 의 용액에 등량의 Ficoll/Sucrose Buffer (90 mM MES-NaOH (pH 6.5), 10 mM Sodium phosphate, 1 mM MgCl2, 0.5 mM EGTA, 0.02 % NaN3, 14 % Ficoll-PM70, 14 % Sucrose) 를 첨가하여 잘 혼합하였다.
(9) 상기 (8) 의 용액을 초고속 원심기 (Hitachi CP80WX, P45AT rotor) 를 사용하여, 25,200 rpm, 10 min, 4 ℃ 에서 초고속 원심 분리를 실시하여, 불요물을 침전으로서 떨어뜨렸다.
(10) 상청의 볼트 획분을 정제용 Buffer A 로 4 배 희석시키고, 초고속 원심기 (Hitachi CP80WX, P45AT rotor) 를 사용하여, 40,000 rpm, 2 시간, 4 ℃ 에서 초고속 원심 분리를 실시하여, 볼트 획분을 침전으로서 떨어뜨렸다.
(11) 침전으로서 얻어진 볼트 획분에 정제용 Buffer A 를 소량 첨가하고, 다운스 호모게나이저로 현탁하였다.
(12) 초고속 원심기 (Hitachi CP80WX, P28S rotor) 의 원심 튜브에 자당의 밀도 구배를 작성하였다. 원심 튜브의 바닥으로부터, 60 %, 50 %, 45 %, 40 %, 30 %, 20 % Sucrose 를 각각 4 ㎖, 5 ㎖, 5 ㎖, 5 ㎖, 5 ㎖, 5 ㎖ 중층하였다. 이것을 4 개 작성하였다.
(13) 상기 (11) 의 용액 5 ㎖ 를 상기 (12) 의 자당 밀도 구배의 20 % 층 상에 중층하였다.
(14) 초고속 원심기 (Hitachi CP80WX, P28S rotor) 를 사용하여, 25,000 rpm, 16 시간, 4 ℃ 에서 초고속 원심 분리를 실시하였다.
(15) 볼트는 40-45 % 획분과 50 % 획분의 일부에 포함되어 있으므로, 이것을 피펫으로 회수하였다. 40, 45 % 획분은 모두 (5 ㎖ 씩), 50 % 획분은 절반 (2.5 ㎖) 을 회수하였다.
(16) 상기 (15) 의 회수액을 정제용 Buffer A 로 4 배 희석시키고, 초고속 원심기 (Hitachi CP80WX, P45AT rotor) 를 사용하여, 40,000 rpm, 2 시간, 4 ℃ 에서 초고속 원심 분리를 실시함으로써, 볼트 획분을 침전으로서 떨어뜨렸다.
(17) 침전으로서 얻어진 볼트 획분에 Buffer A 를 소량 첨가하고, 다운스 호모게나이저로 현탁하였다.
(18) 상기 (17) 의 볼트 시료를 0.22 ㎛ 의 필터에 통과시켜, 먼지 등을 제거하였다.
(19) 겔 여과용 Buffer A (50 mM Tris-HCl (pH 7.5), 75 mM NaCl, 1.5 mM MgCl2, 1 mM DTT) 를 2 베드 볼륨 흘려 평형화한 겔 여과 칼럼 (GE 헬스케어·재팬 (주) 사 제조, Sephacryl S-500, 26/60) 에 상기 (18) 의 시료를 2 ㎖ 어플라이하고, 유속 0.5 ㎖/min 으로 4 ㎖ 씩 분취하였다.
(20) 목적으로 하는 볼트 획분은, 시료 어플라이 후 140 ∼ 190 ㎖ (프랙션 No.39-49) 쯤에 나오므로, 이것을 회수하여, 초고속 원심기 (Hitachi CP80WX, P45AT rotor) 를 사용하여, 40,000 rpm, 2 시간, 4 ℃ 에서 초고속 원심 분리를 실시함으로써, 볼트 획분을 침전으로서 떨어뜨렸다 (90 ∼ 110 ㎖ (프랙션 No.27-30) 쯤에는 볼트의 회합체가 나오므로, 이것을 제거함으로써 균일한 볼트 입자를 얻을 수 있다).
(21) 침전으로서 얻어진 볼트 획분에 Buffer A 를 소량 첨가하고, 다운스 호모게나이저로 현탁하여, 이것을 최종 정제 표품으로 하였다.
여기서, 도 6 의 좌측은 파쇄 (상기 순서 (9)) 후의 SDS-PAGE 의 결과를 나타내는 사진이고, LZMVP_Gly3 에 대한 상청 (레인 A), 침전 (레인 B), LZMVP_Gly6 에 대한 상청 (레인 C), 침전 (레인 D) 을 각각 나타내고 있다. 또 도 6 의 우측은 자당 밀도 구배 원심 분리 (상기 순서 (14)) 후의 SDS-PAGE 의 결과를 나타내는 사진이고, 좌측의 군 a 가 LZMVP_Gly3 에 대한 결과, 우측의 군 b 가 LZMVP_Gly6 에 대한 결과를 각각 나타내고 있다. 또, 도 7 은, LZMVP_Gly3 에 대해, 최종 정제 표품을 나타내는 전자 현미경 사진이다.
[5] 정제된 볼트의 단백질 정량
(1) 피어스사의 BCA Protein Assay Reagent Kit 를 사용하여, 상기 서술한 바와 같이 하여 얻어진 W-MVP, LZMVP_Gly3 및 LZMVP_Gly6 에 대한 단백질 정량을 실시하였다.
(2) 키트의 시약 A 를 5 ㎖, 시약 B 를 100 ㎕, 15 ㎖ 튜브에 넣고, 잘 혼합하였다.
(3) 상기 (2) 의 혼합 용액을 1.5 ㎖ 의 에펜도르프 튜브에 500 ㎕ 넣은 것을 7 개 준비하였다.
(4) 사전에 준비한 5 개의 BSA 표준 용액 (1000, 500, 250, 125, 62.5 ㎍/㎖) 을 각각 25 ㎕ 취해 상기 (3) 의 1.5 ㎖ 튜브에 넣고, 볼텍스로 잘 혼합하였다.
(5) 정량하는 볼트 용액 (W-MVP, LZMVP_Gly3 또는 LZMVP_Gly6 을 포함한다) 을 초순수로 희석시킨 것을 2 종류 만들었다 (예를 들어, 5 배 희석과 10 배 희석, 25 배 희석과 50 배 희석 등).
(6) 상기 (5) 에서 제조한 볼트의 희석 용액 2 종을 각각, 상기 (3) 의 1.5 ㎖ 튜브에 넣고, 볼텍스로 잘 혼합하였다.
(7) 상기 (4) 와 상기 (6) 의 1.5 ㎖ 튜브를 37 ℃ 에서 30 분간 인큐베이트하였다.
(8) 분광 광도계를 사용하여 상기 (7) 의 562 ㎚ 에서의 흡광도를 측정한다 (뷰렛 반응에 의한 환원 Cu (+) 와 비신코닌산 (BCA) 의 배위에 따른 비색 정량).
(9) 먼저, BCA 에 대해 측정 결과를, 세로축을 흡광도, 가로축을 BSA 농도로 하여 플롯하고, 최소제곱법에 의해 근사 곡선 (표준 곡선) 을 구하였다.
(10) 상기 (9) 의 표준 곡선으로부터 볼트의 희석 용액의 농도를 구하고, 희석 배율로부터 볼트 원액의 농도를 구하였다.
(11) 볼트 원액의 농도에 총액량을 곱하여, 볼트의 총 수량을 계산하였다.
(12) 결과, 1 ℓ 배양당, W-볼트 (비교예 1) 는 3 ∼ 5 ㎎ 인 데에 반해, LZ-볼트 (LZMVP_Gly3 (실시예 1), LZMVP_Gly6 (실시예 2)) 에서는 약 10 배를 초과하는 70 ∼ 80 ㎎ 의 수량이 얻어져 있었다.
금회 개시된 실시형태 및 실험예는 모든 면에서 예시로서, 제한적인 것은 아니라고 생각되어야 할 것이다. 본 발명의 범위는 상기한 설명이 아니라 청구의 범위에 의해 나타내어지고, 청구의 범위와 균등한 의미 및 범위 내에서의 모든 변경이 포함되는 것이 의도된다.
1 : 인공 생체 입자
2 : 볼트
3 : MVP
4 : 류신 지퍼
5 : 캡
6 : 숄더
7 : 보디
8 : 웨이스트
9 : 캡 헬릭스
10 : 캡 링
11 : 약제
12 : 항원
13 : 표적 세포
14 : 엔도솜
2 : 볼트
3 : MVP
4 : 류신 지퍼
5 : 캡
6 : 숄더
7 : 보디
8 : 웨이스트
9 : 캡 헬릭스
10 : 캡 링
11 : 약제
12 : 항원
13 : 표적 세포
14 : 엔도솜
SEQUENCE LISTING
<110> Japan Science and Technology Agency
<120> Artificial bioparticle and Producing Method Thereof
<130> 9130412
<140> JP2012-253031
<141> 2012-11-19
<160> 14
<170> PatentIn version 3.1
<210> 1
<211> 281
<212> PRT
<213> Yeast GCNF
<400> 1
Met Ser Glu Tyr Gln Pro Ser Leu Phe Ala Leu Asn Pro Met Gly Phe
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Ser Pro Leu Asp Gly Ser Lys Ser Thr Asn Glu Asn Val Ser Ala Ser
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Thr Ser Thr Ala Lys Pro Met Val Gly Gln Leu Ile Phe Asp Lys Phe
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Ile Lys Thr Glu Glu Asp Pro Ile Ile Lys Gln Asp Thr Pro Ser Asn
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Leu Asp Phe Asp Phe Ala Leu Pro Gln Thr Ala Thr Ala Pro Asp Ala
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Lys Thr Val Leu Pro Ile Pro Glu Leu Asp Asp Ala Val Val Glu Ser
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Phe Phe Ser Ser Ser Thr Asp Ser Thr Pro Met Phe Glu Tyr Glu Asn
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Leu Glu Asp Asn Ser Lys Glu Trp Thr Ser Leu Phe Asp Asn Asp Ile
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Pro Val Thr Thr Asp Asp Val Ser Leu Ala Asp Lys Ala Ile Glu Ser
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Thr Glu Glu Val Ser Leu Val Pro Ser Asn Leu Glu Val Ser Thr Thr
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Ser Phe Leu Pro Thr Pro Val Leu Glu Asp Ala Lys Leu Thr Gln Thr
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Arg Lys Val Lys Lys Pro Asn Ser Val Val Lys Lys Ser His His Val
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Gly Lys Asp Asp Glu Ser Arg Leu Asp His Leu Gly Val Val Ala Tyr
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Asn Arg Lys Gln Arg Ser Ile Pro Leu Ser Pro Ile Val Pro Glu Ser
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Ser Asp Pro Ala Ala Leu Lys Arg Ala Arg Asn Thr Glu Ala Ala Arg
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Arg Ser Arg Ala Arg Lys Leu Gln Arg Met Lys Gln Leu Glu Asp Lys
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Val Glu Glu Leu Leu Ser Lys Asn Tyr His Leu Glu Asn Glu Val Ala
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Arg Leu Lys Lys Leu Val Gly Glu Arg
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Met Arg Met Lys Gln Leu Glu Asp Lys Val Glu Glu Leu Leu Ser Lys
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gaa cgc 102
Glu Arg
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Met Arg Met Lys Gln Leu Glu Asp Lys Val Glu Glu Leu Leu
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Ser Lys Asn Tyr His Leu Glu Asn Glu Val Ala Arg Leu Lys Lys Leu
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gtt ggc gaa cgc gaattc atg gca act gaa gag gcc atc atc cgc atc 144
Val Gly Glu Arg Met Ala Thr Glu Glu Ala Ile Ile Arg Ile
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ccc cca tac cac tac atc cat gtg ctg gac cag aac agt aat gtg tcc 192
Pro Pro Tyr His Tyr Ile His Val Leu Asp Gln Asn Ser Asn Val Ser
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Arg Val Glu Val Gly Pro Lys Thr Tyr Ile Arg Gln Asp Asn Glu Arg
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Val Leu Phe Ala Pro Val Arg Met Val Thr Val Pro Pro Arg His Tyr
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Cys Ile Val Ala Asn Pro Val Ser Arg Asp Thr Gln Ser Ser Val Leu
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Phe Asp Ile Thr Gly Gln Val Arg Leu Arg His Ala Asp Gln Glu Ile
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cga cta gcc cag gac ccc ttc ccc ctg tat cca ggg gag gtg ctg gaa 432
Arg Leu Ala Gln Asp Pro Phe Pro Leu Tyr Pro Gly Glu Val Leu Glu
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Lys Asp Ile Thr Pro Leu Gln Val Val Leu Pro Asn Thr Ala Leu His
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Leu Lys Ala Leu Leu Asp Phe Glu Asp Lys Asn Gly Asp Lys Val Met
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gca gga gac gag tgg cta ttt gag gga cct ggc acc tac atc cca cag 576
Ala Gly Asp Glu Trp Leu Phe Glu Gly Pro Gly Thr Tyr Ile Pro Gln
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aag gaa gtg gaa gtc gtg gag atc att cag gcc aca gtc atc aaa cag 624
Lys Glu Val Glu Val Val Glu Ile Ile Gln Ala Thr Val Ile Lys Gln
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Asn Gln Ala Leu Arg Leu Arg Ala Arg Lys Glu Cys Phe Asp Arg Glu
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ggc aag ggg cgc gtg aca ggt gag gag tgg ctg gtc cga tcc gtg ggg 720
Gly Lys Gly Arg Val Thr Gly Glu Glu Trp Leu Val Arg Ser Val Gly
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Ala Tyr Leu Pro Ala Val Phe Glu Glu Val Leu Asp Leu Val Asp Ala
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Val Ile Leu Thr Glu Lys Thr Ala Leu His Leu Arg Ala Leu Gln Asn
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Phe Arg Asp Leu Arg Gly Val Leu His Arg Thr Gly Glu Glu Trp Leu
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Val Thr Val Gln Asp Thr Glu Ala His Val Pro Asp Val Tyr Glu Glu
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Val Leu Gly Val Val Pro Ile Thr Thr Leu Gly Pro Arg His Tyr Cys
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Val Ile Leu Asp Pro Met Gly Pro Asp Gly Lys Asn Gln Leu Gly Gln
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Lys Arg Val Val Lys Gly Glu Lys Ser Phe Phe Leu Gln Pro Gly Glu
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Arg Leu Glu Arg Gly Ile Gln Asp Val Tyr Val Leu Ser Glu Gln Gln
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Gly Leu Leu Leu Lys Ala Leu Gln Pro Leu Glu Glu Gly Glu Ser Glu
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Glu Lys Val Ser His Gln Ala Gly Asp Cys Trp Leu Ile Arg Gly Pro
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ctg gag tat gtg cca tct gca aaa gtg gag gtg gtg gag gag cgt cag 1248
Leu Glu Tyr Val Pro Ser Ala Lys Val Glu Val Val Glu Glu Arg Gln
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Ala Ile Pro Leu Asp Gln Asn Glu Gly Ile Tyr Val Gln Asp Val Lys
415 420 425
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Thr Gly Lys Val Arg Ala Val Ile Gly Ser Thr Tyr Met Leu Thr Gln
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Asp Glu Val Leu Trp Glu Lys Glu Leu Pro Ser Gly Val Glu Glu Leu
445 450 455 460
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Leu Asn Leu Gly His Asp Pro Leu Ala Asp Arg Gly Gln Lys Gly Thr
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Ala Lys Pro Leu Gln Pro Ser Ala Pro Arg Asn Lys Thr Arg Val Val
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Ser Tyr Arg Val Pro His Asn Ala Ala Val Gln Val Tyr Asp Tyr Arg
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Ala Lys Arg Ala Arg Val Val Phe Gly Pro Glu Leu Val Thr Leu Asp
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Pro Glu Glu Gln Phe Thr Val Leu Ser Leu Ser Ala Gly Arg Pro Lys
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cgt cct cat gcc cgc cgt gca ctc tgc cta ctg ctg gga cct gat ttc 1680
Arg Pro His Ala Arg Arg Ala Leu Cys Leu Leu Leu Gly Pro Asp Phe
545 550 555
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Phe Thr Asp Val Ile Thr Ile Glu Thr Ala Asp His Ala Arg Leu Gln
560 565 570
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Leu Gln Leu Ala Tyr Asn Trp His Phe Glu Leu Lys Asn Arg Asn Asp
575 580 585
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Pro Ala Glu Ala Ala Lys Leu Phe Ser Val Pro Asp Phe Val Gly Asp
590 595 600
gcc tgc aag gcc att gca tcc cga gtc cgg ggg gct gta gcc tct gtc 1872
Ala Cys Lys Ala Ile Ala Ser Arg Val Arg Gly Ala Val Ala Ser Val
605 610 615 620
acc ttt gat gac ttc cat aaa aac tca gcc cgg atc att cga atg gct 1920
Thr Phe Asp Asp Phe His Lys Asn Ser Ala Arg Ile Ile Arg Met Ala
625 630 635
gtt ttt ggc ttt gag atg tct gaa gac aca ggt cct gat ggc aca ctc 1968
Val Phe Gly Phe Glu Met Ser Glu Asp Thr Gly Pro Asp Gly Thr Leu
640 645 650
ctg ccc aag gct cga gac cag gca gtc ttt ccc caa aac ggg ctg gta 2016
Leu Pro Lys Ala Arg Asp Gln Ala Val Phe Pro Gln Asn Gly Leu Val
655 660 665
gtc agc agt gtg gat gtg cag tca gtg gag ccc gtg gac cag agg acc 2064
Val Ser Ser Val Asp Val Gln Ser Val Glu Pro Val Asp Gln Arg Thr
670 675 680
cgg gat gcc ctt cag cgc agc gtt cag ctg gcc atc gaa att acc acc 2112
Arg Asp Ala Leu Gln Arg Ser Val Gln Leu Ala Ile Glu Ile Thr Thr
685 690 695 700
aac tcc cag gag gca gca gcc aag cac gag gct cag aga ctg gaa cag 2160
Asn Ser Gln Glu Ala Ala Ala Lys His Glu Ala Gln Arg Leu Glu Gln
705 710 715
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Glu Ala Arg Gly Arg Leu Glu Arg Gln Lys Ile Leu Asp Gln Ser Glu
720 725 730
gct gaa aaa gcc cgc aag gaa ctc ttg gag ctt gag gct atg agc atg 2256
Ala Glu Lys Ala Arg Lys Glu Leu Leu Glu Leu Glu Ala Met Ser Met
735 740 745
gct gtg gag agc acg ggt aat gcc aaa gca gag gct gag tcc cgt gca 2304
Ala Val Glu Ser Thr Gly Asn Ala Lys Ala Glu Ala Glu Ser Arg Ala
750 755 760
gag gca gcg agg atc gaa gga gaa ggc tct gtg ctg cag gcc aag ctc 2352
Glu Ala Ala Arg Ile Glu Gly Glu Gly Ser Val Leu Gln Ala Lys Leu
765 770 775 780
aag gca cag gcg cta gcc att gag acg gag gct gag ttg gag cga gta 2400
Lys Ala Gln Ala Leu Ala Ile Glu Thr Glu Ala Glu Leu Glu Arg Val
785 790 795
aag aaa gta cga gag atg gaa ctg atc tat gcc cgg gcc cag ttg gag 2448
Lys Lys Val Arg Glu Met Glu Leu Ile Tyr Ala Arg Ala Gln Leu Glu
800 805 810
ctg gag gtg agc aag gcg cag cag ctt gcc aat gtg gag gca aag aag 2496
Leu Glu Val Ser Lys Ala Gln Gln Leu Ala Asn Val Glu Ala Lys Lys
815 820 825
ttc aag gag atg aca gag gca ctg ggc ccc ggc acc atc agg gac ctg 2544
Phe Lys Glu Met Thr Glu Ala Leu Gly Pro Gly Thr Ile Arg Asp Leu
830 835 840
gct gtg gcc ggg cca gag atg cag gtg aaa ctt ctc cag tcc ctg ggc 2592
Ala Val Ala Gly Pro Glu Met Gln Val Lys Leu Leu Gln Ser Leu Gly
845 850 855 860
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Leu Lys Ser Thr Leu Ile Thr Asp Gly Ser Ser Pro Ile Asn Leu Phe
865 870 875
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Ser Thr Ala Phe Gly Leu Leu Gly Leu Gly Ser Asp Gly Gln Pro Pro
880 885 890
gca cag aag tga 2700
Ala Gln Lys
895
<210> 7
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<212> PRT
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<223> Leucine Zipper and MVP
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Met Arg Met Lys Gln Leu Glu Asp Lys Val Glu Glu Leu Leu Ser Lys
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Asn Tyr His Leu Glu Asn Glu Val Ala Arg Leu Lys Lys Leu Val Gly
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Glu Arg
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Met Ala Thr Glu Glu Ala Ile Ile Arg Ile Pro Pro Tyr His Tyr Ile
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His Val Leu Asp Gln Asn Ser Asn Val Ser Arg Val Glu Val Gly Pro
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Lys Thr Tyr Ile Arg Gln Asp Asn Glu Arg Val Leu Phe Ala Pro Val
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Arg Met Val Thr Val Pro Pro Arg His Tyr Cys Ile Val Ala Asn Pro
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Val Ser Arg Asp Thr Gln Ser Ser Val Leu Phe Asp Ile Thr Gly Gln
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Phe Pro Leu Tyr Pro Gly Glu Val Leu Glu Lys Asp Ile Thr Pro Leu
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Gln Val Val Leu Pro Asn Thr Ala Leu His Leu Lys Ala Leu Leu Asp
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Phe Glu Asp Lys Asn Gly Asp Lys Val Met Ala Gly Asp Glu Trp Leu
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Phe Glu Gly Pro Gly Thr Tyr Ile Pro Gln Lys Glu Val Glu Val Val
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Glu Ile Ile Gln Ala Thr Val Ile Lys Gln Asn Gln Ala Leu Arg Leu
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Arg Ala Arg Lys Glu Cys Phe Asp Arg Glu Gly Lys Gly Arg Val Thr
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Gly Glu Glu Trp Leu Val Arg Ser Val Gly Ala Tyr Leu Pro Ala Val
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Phe Glu Glu Val Leu Asp Leu Val Asp Ala Val Ile Leu Thr Glu Lys
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Thr Ala Leu His Leu Arg Ala Leu Gln Asn Phe Arg Asp Leu Arg Gly
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Val Leu His Arg Thr Gly Glu Glu Trp Leu Val Thr Val Gln Asp Thr
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Glu Ala His Val Pro Asp Val Tyr Glu Glu Val Leu Gly Val Val Pro
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Ile Thr Thr Leu Gly Pro Arg His Tyr Cys Val Ile Leu Asp Pro Met
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Gly Pro Asp Gly Lys Asn Gln Leu Gly Gln Lys Arg Val Val Lys Gly
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Glu Lys Ser Phe Phe Leu Gln Pro Gly Glu Arg Leu Glu Arg Gly Ile
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Gln Asp Val Tyr Val Leu Ser Glu Gln Gln Gly Leu Leu Leu Lys Ala
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Leu Gln Pro Leu Glu Glu Gly Glu Ser Glu Glu Lys Val Ser His Gln
340 345 350
Ala Gly Asp Cys Trp Leu Ile Arg Gly Pro Leu Glu Tyr Val Pro Ser
355 360 365
Ala Lys Val Glu Val Val Glu Glu Arg Gln Ala Ile Pro Leu Asp Gln
370 375 380
Asn Glu Gly Ile Tyr Val Gln Asp Val Lys Thr Gly Lys Val Arg Ala
385 390 395 400
Val Ile Gly Ser Thr Tyr Met Leu Thr Gln Asp Glu Val Leu Trp Glu
405 410 415
Lys Glu Leu Pro Ser Gly Val Glu Glu Leu Leu Asn Leu Gly His Asp
420 425 430
Pro Leu Ala Asp Arg Gly Gln Lys Gly Thr Ala Lys Pro Leu Gln Pro
435 440 445
Ser Ala Pro Arg Asn Lys Thr Arg Val Val Ser Tyr Arg Val Pro His
450 455 460
Asn Ala Ala Val Gln Val Tyr Asp Tyr Arg Ala Lys Arg Ala Arg Val
465 470 475 480
Val Phe Gly Pro Glu Leu Val Thr Leu Asp Pro Glu Glu Gln Phe Thr
485 490 495
Val Leu Ser Leu Ser Ala Gly Arg Pro Lys Arg Pro His Ala Arg Arg
500 505 510
Ala Leu Cys Leu Leu Leu Gly Pro Asp Phe Phe Thr Asp Val Ile Thr
515 520 525
Ile Glu Thr Ala Asp His Ala Arg Leu Gln Leu Gln Leu Ala Tyr Asn
530 535 540
Trp His Phe Glu Leu Lys Asn Arg Asn Asp Pro Ala Glu Ala Ala Lys
545 550 555 560
Leu Phe Ser Val Pro Asp Phe Val Gly Asp Ala Cys Lys Ala Ile Ala
565 570 575
Ser Arg Val Arg Gly Ala Val Ala Ser Val Thr Phe Asp Asp Phe His
580 585 590
Lys Asn Ser Ala Arg Ile Ile Arg Met Ala Val Phe Gly Phe Glu Met
595 600 605
Ser Glu Asp Thr Gly Pro Asp Gly Thr Leu Leu Pro Lys Ala Arg Asp
610 615 620
Gln Ala Val Phe Pro Gln Asn Gly Leu Val Val Ser Ser Val Asp Val
625 630 635 640
Gln Ser Val Glu Pro Val Asp Gln Arg Thr Arg Asp Ala Leu Gln Arg
645 650 655
Ser Val Gln Leu Ala Ile Glu Ile Thr Thr Asn Ser Gln Glu Ala Ala
660 665 670
Ala Lys His Glu Ala Gln Arg Leu Glu Gln Glu Ala Arg Gly Arg Leu
675 680 685
Glu Arg Gln Lys Ile Leu Asp Gln Ser Glu Ala Glu Lys Ala Arg Lys
690 695 700
Glu Leu Leu Glu Leu Glu Ala Met Ser Met Ala Val Glu Ser Thr Gly
705 710 715 720
Asn Ala Lys Ala Glu Ala Glu Ser Arg Ala Glu Ala Ala Arg Ile Glu
725 730 735
Gly Glu Gly Ser Val Leu Gln Ala Lys Leu Lys Ala Gln Ala Leu Ala
740 745 750
Ile Glu Thr Glu Ala Glu Leu Glu Arg Val Lys Lys Val Arg Glu Met
755 760 765
Glu Leu Ile Tyr Ala Arg Ala Gln Leu Glu Leu Glu Val Ser Lys Ala
770 775 780
Gln Gln Leu Ala Asn Val Glu Ala Lys Lys Phe Lys Glu Met Thr Glu
785 790 795 800
Ala Leu Gly Pro Gly Thr Ile Arg Asp Leu Ala Val Ala Gly Pro Glu
805 810 815
Met Gln Val Lys Leu Leu Gln Ser Leu Gly Leu Lys Ser Thr Leu Ile
820 825 830
Thr Asp Gly Ser Ser Pro Ile Asn Leu Phe Ser Thr Ala Phe Gly Leu
835 840 845
Leu Gly Leu Gly Ser Asp Gly Gln Pro Pro Ala Gln Lys
850 855 860
<210> 9
<211> 898
<212> PRT
<213> Artificial
<220>
<223> LZ-MVPiGly Linker 3 Residurej
<400> 9
Met Arg Met Lys Gln Leu Glu Asp Lys Val Glu Glu Leu Leu Ser Lys
1 5 10 15
Asn Tyr His Leu Glu Asn Glu Val Ala Arg Leu Lys Lys Leu Val Gly
20 25 30
Glu Arg Gly Gly Gly Met Ala Thr Glu Glu Ala Ile Ile Arg Ile Pro
35 40 45
Pro Tyr His Tyr Ile His Val Leu Asp Gln Asn Ser Asn Val Ser Arg
50 55 60
Val Glu Val Gly Pro Lys Thr Tyr Ile Arg Gln Asp Asn Glu Arg Val
65 70 75 80
Leu Phe Ala Pro Val Arg Met Val Thr Val Pro Pro Arg His Tyr Cys
85 90 95
Ile Val Ala Asn Pro Val Ser Arg Asp Thr Gln Ser Ser Val Leu Phe
100 105 110
Asp Ile Thr Gly Gln Val Arg Leu Arg His Ala Asp Gln Glu Ile Arg
115 120 125
Leu Ala Gln Asp Pro Phe Pro Leu Tyr Pro Gly Glu Val Leu Glu Lys
130 135 140
Asp Ile Thr Pro Leu Gln Val Val Leu Pro Asn Thr Ala Leu His Leu
145 150 155 160
Lys Ala Leu Leu Asp Phe Glu Asp Lys Asn Gly Asp Lys Val Met Ala
165 170 175
Gly Asp Glu Trp Leu Phe Glu Gly Pro Gly Thr Tyr Ile Pro Gln Lys
180 185 190
Glu Val Glu Val Val Glu Ile Ile Gln Ala Thr Val Ile Lys Gln Asn
195 200 205
Gln Ala Leu Arg Leu Arg Ala Arg Lys Glu Cys Phe Asp Arg Glu Gly
210 215 220
Lys Gly Arg Val Thr Gly Glu Glu Trp Leu Val Arg Ser Val Gly Ala
225 230 235 240
Tyr Leu Pro Ala Val Phe Glu Glu Val Leu Asp Leu Val Asp Ala Val
245 250 255
Ile Leu Thr Glu Lys Thr Ala Leu His Leu Arg Ala Leu Gln Asn Phe
260 265 270
Arg Asp Leu Arg Gly Val Leu His Arg Thr Gly Glu Glu Trp Leu Val
275 280 285
Thr Val Gln Asp Thr Glu Ala His Val Pro Asp Val Tyr Glu Glu Val
290 295 300
Leu Gly Val Val Pro Ile Thr Thr Leu Gly Pro Arg His Tyr Cys Val
305 310 315 320
Ile Leu Asp Pro Met Gly Pro Asp Gly Lys Asn Gln Leu Gly Gln Lys
325 330 335
Arg Val Val Lys Gly Glu Lys Ser Phe Phe Leu Gln Pro Gly Glu Arg
340 345 350
Leu Glu Arg Gly Ile Gln Asp Val Tyr Val Leu Ser Glu Gln Gln Gly
355 360 365
Leu Leu Leu Lys Ala Leu Gln Pro Leu Glu Glu Gly Glu Ser Glu Glu
370 375 380
Lys Val Ser His Gln Ala Gly Asp Cys Trp Leu Ile Arg Gly Pro Leu
385 390 395 400
Glu Tyr Val Pro Ser Ala Lys Val Glu Val Val Glu Glu Arg Gln Ala
405 410 415
Ile Pro Leu Asp Gln Asn Glu Gly Ile Tyr Val Gln Asp Val Lys Thr
420 425 430
Gly Lys Val Arg Ala Val Ile Gly Ser Thr Tyr Met Leu Thr Gln Asp
435 440 445
Glu Val Leu Trp Glu Lys Glu Leu Pro Ser Gly Val Glu Glu Leu Leu
450 455 460
Asn Leu Gly His Asp Pro Leu Ala Asp Arg Gly Gln Lys Gly Thr Ala
465 470 475 480
Lys Pro Leu Gln Pro Ser Ala Pro Arg Asn Lys Thr Arg Val Val Ser
485 490 495
Tyr Arg Val Pro His Asn Ala Ala Val Gln Val Tyr Asp Tyr Arg Ala
500 505 510
Lys Arg Ala Arg Val Val Phe Gly Pro Glu Leu Val Thr Leu Asp Pro
515 520 525
Glu Glu Gln Phe Thr Val Leu Ser Leu Ser Ala Gly Arg Pro Lys Arg
530 535 540
Pro His Ala Arg Arg Ala Leu Cys Leu Leu Leu Gly Pro Asp Phe Phe
545 550 555 560
Thr Asp Val Ile Thr Ile Glu Thr Ala Asp His Ala Arg Leu Gln Leu
565 570 575
Gln Leu Ala Tyr Asn Trp His Phe Glu Leu Lys Asn Arg Asn Asp Pro
580 585 590
Ala Glu Ala Ala Lys Leu Phe Ser Val Pro Asp Phe Val Gly Asp Ala
595 600 605
Cys Lys Ala Ile Ala Ser Arg Val Arg Gly Ala Val Ala Ser Val Thr
610 615 620
Phe Asp Asp Phe His Lys Asn Ser Ala Arg Ile Ile Arg Met Ala Val
625 630 635 640
Phe Gly Phe Glu Met Ser Glu Asp Thr Gly Pro Asp Gly Thr Leu Leu
645 650 655
Pro Lys Ala Arg Asp Gln Ala Val Phe Pro Gln Asn Gly Leu Val Val
660 665 670
Ser Ser Val Asp Val Gln Ser Val Glu Pro Val Asp Gln Arg Thr Arg
675 680 685
Asp Ala Leu Gln Arg Ser Val Gln Leu Ala Ile Glu Ile Thr Thr Asn
690 695 700
Ser Gln Glu Ala Ala Ala Lys His Glu Ala Gln Arg Leu Glu Gln Glu
705 710 715 720
Ala Arg Gly Arg Leu Glu Arg Gln Lys Ile Leu Asp Gln Ser Glu Ala
725 730 735
Glu Lys Ala Arg Lys Glu Leu Leu Glu Leu Glu Ala Met Ser Met Ala
740 745 750
Val Glu Ser Thr Gly Asn Ala Lys Ala Glu Ala Glu Ser Arg Ala Glu
755 760 765
Ala Ala Arg Ile Glu Gly Glu Gly Ser Val Leu Gln Ala Lys Leu Lys
770 775 780
Ala Gln Ala Leu Ala Ile Glu Thr Glu Ala Glu Leu Glu Arg Val Lys
785 790 795 800
Lys Val Arg Glu Met Glu Leu Ile Tyr Ala Arg Ala Gln Leu Glu Leu
805 810 815
Glu Val Ser Lys Ala Gln Gln Leu Ala Asn Val Glu Ala Lys Lys Phe
820 825 830
Lys Glu Met Thr Glu Ala Leu Gly Pro Gly Thr Ile Arg Asp Leu Ala
835 840 845
Val Ala Gly Pro Glu Met Gln Val Lys Leu Leu Gln Ser Leu Gly Leu
850 855 860
Lys Ser Thr Leu Ile Thr Asp Gly Ser Ser Pro Ile Asn Leu Phe Ser
865 870 875 880
Thr Ala Phe Gly Leu Leu Gly Leu Gly Ser Asp Gly Gln Pro Pro Ala
885 890 895
Gln Lys
<210> 10
<211> 901
<212> PRT
<213> Artificial
<220>
<223> LZ-MVPiGly Linker 6 Residurej
<400> 10
Met Arg Met Lys Gln Leu Glu Asp Lys Val Glu Glu Leu Leu Ser Lys
1 5 10 15
Asn Tyr His Leu Glu Asn Glu Val Ala Arg Leu Lys Lys Leu Val Gly
20 25 30
Glu Arg Gly Gly Gly Gly Gly Gly Met Ala Thr Glu Glu Ala Ile Ile
35 40 45
Arg Ile Pro Pro Tyr His Tyr Ile His Val Leu Asp Gln Asn Ser Asn
50 55 60
Val Ser Arg Val Glu Val Gly Pro Lys Thr Tyr Ile Arg Gln Asp Asn
65 70 75 80
Glu Arg Val Leu Phe Ala Pro Val Arg Met Val Thr Val Pro Pro Arg
85 90 95
His Tyr Cys Ile Val Ala Asn Pro Val Ser Arg Asp Thr Gln Ser Ser
100 105 110
Val Leu Phe Asp Ile Thr Gly Gln Val Arg Leu Arg His Ala Asp Gln
115 120 125
Glu Ile Arg Leu Ala Gln Asp Pro Phe Pro Leu Tyr Pro Gly Glu Val
130 135 140
Leu Glu Lys Asp Ile Thr Pro Leu Gln Val Val Leu Pro Asn Thr Ala
145 150 155 160
Leu His Leu Lys Ala Leu Leu Asp Phe Glu Asp Lys Asn Gly Asp Lys
165 170 175
Val Met Ala Gly Asp Glu Trp Leu Phe Glu Gly Pro Gly Thr Tyr Ile
180 185 190
Pro Gln Lys Glu Val Glu Val Val Glu Ile Ile Gln Ala Thr Val Ile
195 200 205
Lys Gln Asn Gln Ala Leu Arg Leu Arg Ala Arg Lys Glu Cys Phe Asp
210 215 220
Arg Glu Gly Lys Gly Arg Val Thr Gly Glu Glu Trp Leu Val Arg Ser
225 230 235 240
Val Gly Ala Tyr Leu Pro Ala Val Phe Glu Glu Val Leu Asp Leu Val
245 250 255
Asp Ala Val Ile Leu Thr Glu Lys Thr Ala Leu His Leu Arg Ala Leu
260 265 270
Gln Asn Phe Arg Asp Leu Arg Gly Val Leu His Arg Thr Gly Glu Glu
275 280 285
Trp Leu Val Thr Val Gln Asp Thr Glu Ala His Val Pro Asp Val Tyr
290 295 300
Glu Glu Val Leu Gly Val Val Pro Ile Thr Thr Leu Gly Pro Arg His
305 310 315 320
Tyr Cys Val Ile Leu Asp Pro Met Gly Pro Asp Gly Lys Asn Gln Leu
325 330 335
Gly Gln Lys Arg Val Val Lys Gly Glu Lys Ser Phe Phe Leu Gln Pro
340 345 350
Gly Glu Arg Leu Glu Arg Gly Ile Gln Asp Val Tyr Val Leu Ser Glu
355 360 365
Gln Gln Gly Leu Leu Leu Lys Ala Leu Gln Pro Leu Glu Glu Gly Glu
370 375 380
Ser Glu Glu Lys Val Ser His Gln Ala Gly Asp Cys Trp Leu Ile Arg
385 390 395 400
Gly Pro Leu Glu Tyr Val Pro Ser Ala Lys Val Glu Val Val Glu Glu
405 410 415
Arg Gln Ala Ile Pro Leu Asp Gln Asn Glu Gly Ile Tyr Val Gln Asp
420 425 430
Val Lys Thr Gly Lys Val Arg Ala Val Ile Gly Ser Thr Tyr Met Leu
435 440 445
Thr Gln Asp Glu Val Leu Trp Glu Lys Glu Leu Pro Ser Gly Val Glu
450 455 460
Glu Leu Leu Asn Leu Gly His Asp Pro Leu Ala Asp Arg Gly Gln Lys
465 470 475 480
Gly Thr Ala Lys Pro Leu Gln Pro Ser Ala Pro Arg Asn Lys Thr Arg
485 490 495
Val Val Ser Tyr Arg Val Pro His Asn Ala Ala Val Gln Val Tyr Asp
500 505 510
Tyr Arg Ala Lys Arg Ala Arg Val Val Phe Gly Pro Glu Leu Val Thr
515 520 525
Leu Asp Pro Glu Glu Gln Phe Thr Val Leu Ser Leu Ser Ala Gly Arg
530 535 540
Pro Lys Arg Pro His Ala Arg Arg Ala Leu Cys Leu Leu Leu Gly Pro
545 550 555 560
Asp Phe Phe Thr Asp Val Ile Thr Ile Glu Thr Ala Asp His Ala Arg
565 570 575
Leu Gln Leu Gln Leu Ala Tyr Asn Trp His Phe Glu Leu Lys Asn Arg
580 585 590
Asn Asp Pro Ala Glu Ala Ala Lys Leu Phe Ser Val Pro Asp Phe Val
595 600 605
Gly Asp Ala Cys Lys Ala Ile Ala Ser Arg Val Arg Gly Ala Val Ala
610 615 620
Ser Val Thr Phe Asp Asp Phe His Lys Asn Ser Ala Arg Ile Ile Arg
625 630 635 640
Met Ala Val Phe Gly Phe Glu Met Ser Glu Asp Thr Gly Pro Asp Gly
645 650 655
Thr Leu Leu Pro Lys Ala Arg Asp Gln Ala Val Phe Pro Gln Asn Gly
660 665 670
Leu Val Val Ser Ser Val Asp Val Gln Ser Val Glu Pro Val Asp Gln
675 680 685
Arg Thr Arg Asp Ala Leu Gln Arg Ser Val Gln Leu Ala Ile Glu Ile
690 695 700
Thr Thr Asn Ser Gln Glu Ala Ala Ala Lys His Glu Ala Gln Arg Leu
705 710 715 720
Glu Gln Glu Ala Arg Gly Arg Leu Glu Arg Gln Lys Ile Leu Asp Gln
725 730 735
Ser Glu Ala Glu Lys Ala Arg Lys Glu Leu Leu Glu Leu Glu Ala Met
740 745 750
Ser Met Ala Val Glu Ser Thr Gly Asn Ala Lys Ala Glu Ala Glu Ser
755 760 765
Arg Ala Glu Ala Ala Arg Ile Glu Gly Glu Gly Ser Val Leu Gln Ala
770 775 780
Lys Leu Lys Ala Gln Ala Leu Ala Ile Glu Thr Glu Ala Glu Leu Glu
785 790 795 800
Arg Val Lys Lys Val Arg Glu Met Glu Leu Ile Tyr Ala Arg Ala Gln
805 810 815
Leu Glu Leu Glu Val Ser Lys Ala Gln Gln Leu Ala Asn Val Glu Ala
820 825 830
Lys Lys Phe Lys Glu Met Thr Glu Ala Leu Gly Pro Gly Thr Ile Arg
835 840 845
Asp Leu Ala Val Ala Gly Pro Glu Met Gln Val Lys Leu Leu Gln Ser
850 855 860
Leu Gly Leu Lys Ser Thr Leu Ile Thr Asp Gly Ser Ser Pro Ile Asn
865 870 875 880
Leu Phe Ser Thr Ala Phe Gly Leu Leu Gly Leu Gly Ser Asp Gly Gln
885 890 895
Pro Pro Ala Gln Lys
900
<210> 11
<211> 20
<212> DNA
<213> Artificial
<220>
<223> forward primerilzmvp_0g_fj
<400> 11
atggcaactg aagaggccat 20
<210> 12
<211> 39
<212> DNA
<213> Artificial
<220>
<223> forward primerilzmvp_3g_fj
<400> 12
ggcggcggca tggcaactga agaggccatc atccgcatc 39
<210> 13
<211> 39
<212> DNA
<213> Artificial
<220>
<223> reverse primerilzmvp_3g_rj
<400> 13
gccagattaa agaaattagt tggcgaacgc ggcggcggc 39
<210> 14
<211> 39
<212> DNA
<213> Artificial
<220>
<223> Complementary Sequence of Reverse Primer
<400> 14
gccgccgccg cgttcgccaa ctaatttctt taatctggc 39
Claims (6)
- 볼트 (Vault) 의 웨이스트 (Waist) 를 구성하는 MVP (Major Vault Protein) 의 N 말단 각각에 류신 지퍼가 도입된 것을 특징으로 하는 인공 생체 입자로서,
MVP 의 N 말단과 류신 지퍼 사이에 링커가 개재되어 있는 인공 생체 입자. - 삭제
- 제 1 항에 있어서,
상기 링커가 3 ∼ 6 개의 글리신인 인공 생체 입자. - 제 1 항에 있어서,
류신 지퍼가 효모의 전사 활성화 인자 GCN4 유래인 인공 생체 입자. - 제 1 항, 제 3 항 및 제 4 항 중 어느 한 항에 기재된 인공 생체 입자를 제조하는 방법으로서,
류신 지퍼 유전자를 MVP 유전자의 N 말단이 되는 측에 도입하여 발현시키는 인공 생체 입자의 제조 방법. - 제 5 항에 있어서,
MVP 유전자와 류신 지퍼 유전자를, 제한 효소 사이트를 개재하지 않고, 링커를 코드하는 유전자로 연결시키는 것을 특징으로 하는 인공 생체 입자의 제조 방법.
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CN104797709A (zh) | 2015-07-22 |
EP2921555A4 (en) | 2016-06-01 |
JP5591418B1 (ja) | 2014-09-17 |
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